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AnteayerInternational Wound Journal

Combining antibiotic‐loaded bone cement‐based free vastus lateralis muscle‐sparing flap with split‐thickness skin grafts: A reliable strategy for reconstructing diabetic foot ulcers at non‐weight‐bearing areas

Abstract

Diabetic foot ulcers (DFUs) present significant challenges due to their associated amputation rates, mortality, treatment complexity and excessive costs. Our earlier work introduced a wound surgical integrated treatment (WSIT) for DFUs, yielding promising outcomes. This study focuses on a specific WSIT protocol employing antibiotic-loaded bone cement (ALBC) in the first Stage, and free vastus lateralis muscle-sparing (VLMS) flaps and split-thickness skin grafts (STSGs) in the second stage to repair non-weight-bearing DFUs. From July 2021 to July 2023, seven DFU patients (aged 47–71 years) underwent this treatment. Demographic data, hospital stay and repair surgery times were collected. Histological and immunohistochemical analyses assessed angiogenesis, collagen deposition and inflammation. SF-36 questionnaire measured pre- and postoperative quality of life. Preoperative ultrasound Doppler showed that the peak blood flow velocity of the recipient area artery was significantly >30 cm/s (38.6 ± 6.8 cm/s) in all patients. Muscle flap sizes varied from 8 × 3.5 × 1 to 18 × 6 × 2 cm. The operation time of the repair surgery was 156.9 ± 15.08 minutes, and the hospital stay was 18.9 ± 3.3 days. Histological analysis proved that covering DFUs with ALBC induced membrane formation and increased collagen, neovascularization and M2 macrophages fraction while reducing M1 macrophages one. All grafts survived without amputation during a 7- to 24-month follow-up, during which SF-36 scores significantly improved. A combination of ALBC with free VLMS flaps and STSGs proved to be safe and effective for reconstructing non-weight-bearing DFUs. It rapidly controlled infection, enhanced life quality and foot function, and reduced hospitalization time. We advocate integrating this strategy into DFU treatment plans.

A purified reconstituted bilayer matrix shows improved outcomes in treatment of non‐healing diabetic foot ulcers when compared to the standard of care: Final results and analysis of a prospective, randomized, controlled, multi‐centre clinical trial

Abstract

As the incidence of diabetic foot ulcers (DFU) increases, better treatments that improve healing should reduce complications of these ulcers including infections and amputations. We conducted a randomized controlled trial comparing outcomes between a novel purified reconstituted bilayer membrane (PRBM) to the standard of care (SOC) in the treatment of non-healing DFUs. This study included 105 patients who were randomized to either of two treatment groups (n = 54 PRBM; n = 51 SOC) in the intent to treat (ITT) group and 80 who completed the study per protocol (PP) (n = 47 PRBM; n = 33 SOC). The primary endpoint was the percentage of wounds closed after 12 weeks. Secondary outcomes included percent area reduction, time to healing, quality of life, and cost to closure. The DFUs that had been treated with PRBM healed at a higher rate than those treated with SOC (ITT: 83% vs. 45%, p = 0.00004, PP: 92% vs. 67%, p = 0.005). Wounds treated with PRBM also healed significantly faster than those treated with SOC with a mean of 42 versus 62 days for SOC (p = 0.00074) and achieved a mean wound area reduction within 12 weeks of 94% versus 51% for SOC (p = 0.0023). There were no adverse events or serious adverse events that were related to either the PRBM or the SOC. In comparison to the SOC, DFUs healed faster when treated with PRBM. Thus, the use of this PRBM is an effective option for the treatment of chronic DFUs.

The triglyceride glucose index as a sensitive predictor for the risk of MACCEs in patients with diabetic foot ulcers: An ambispective longitudinal cohort study

Abstract

The triglyceride glucose (TyG) index has been confirmed a predictive value for type 2 diabetes mellitus (T2DM). However, no research has yet confirmed whether there is a linear correlation between the TyG index and MACCEs in DFUs. The present study aimed to delve into the association between the TyG index and the risk of MACCEs in patients with DFUs. A total of 960 inpatients with DFUs were recruited. All participants were followed up every 6 months for 11 years with a median of 83 months. According to the cut-off value of the TyG index acquired from receiver operating characteristic (ROC) analysis, the subjects were divided into two groups: low-level (<9.12, n = 480) and high-level (≥9.12, n = 480). The relationship between the TyG index and MACCEs was evaluated by the multivariable Cox regression model, restricted cubic spline (RCS) model, stratified analysis and the Kaplan–Meier survival analysis. Out of 960 participants, 271 experienced MACCEs (28.22%), of whom 79 (29.15%) died. ROC analysis got the optimal TyG index cut-off value of 9.12. Multivariable Cox regression analysis combined with the RCS model showed that the TyG index was positively associated with MACCEs in an S-shaped non-linear dose-dependent manner within the range of TyG index 7.5–9.5 (p < 0.001). The Kaplan–Meier survival analysis indicated the higher the TyG index, the greater the cumulative incidence of MACCEs (log-rank, p < 0.001). The study first confirmed an S-shaped non-linear dose-dependent positive relationship between the TyG index and the risk of MACCEs in DFUs. Consequently, lowering the TyG index level aids in improving the prognosis of patients with DFUs.

Topical pravibismane as adjunctive therapy for moderate or severe diabetic foot infections: A phase 1b randomized, multicenter, double‐blind, placebo‐controlled trial

Abstract

This Phase 1b study was designed to evaluate the safety and efficacy of pravibismane, a novel broad-spectrum topical anti-infective, in managing moderate or severe chronic diabetic foot ulcer (DFU) infections. This randomized, double-blind, placebo-controlled, multicenter study consisted of 39 individuals undergoing pravibismane treatment and 13 individuals in the placebo group. Assessment of safety parameters included clinical observations of tolerability and pharmacokinetics from whole blood samples. Pravibismane was well-tolerated and exhibited minimal systemic absorption, as confirmed by blood concentrations that were below the lower limit of quantitation (0.5 ng/mL) or in the low nanomolar range, which is orders of magnitude below the threshold of pharmacological relevance for pravibismane. Pravibismane treated subjects showed approximately 3-fold decrease in ulcer size compared to the placebo group (85% vs. 30%, p = 0.27). Furthermore, the incidence of ulcer-related lower limb amputations was approximately 6-fold lower (2.6%) in the pooled pravibismane group versus 15.4% in the placebo group (p = 0.15). There were no treatment emergent or serious adverse events related to study drug. The initial findings indicate that topical pravibismane was safe and potentially effective treatment for improving recovery from infected chronic ulcers by reducing ulcer size and facilitating wound healing in infected DFUs (ClinicalTrials.gov Identifier NCT02723539).

Application of hyperbaric oxygen therapy in diabetic foot ulcers: A meta‐analysis

Abstract

Hyperbaric oxygen therapy (HBOT) has been used in patients with diabetic foot ulcers (DFU) for many years, but its clinical efficacy is still controversial. Therefore, this study explored the efficacy of HBOT applied to DFU by means of meta-analysis. PubMed, Cochrane Library, Embase, CNKI and Wanfang databases were searched, from database inception to October 2023, and published randomised controlled trials (RCTs) of HBOT in DFU were collected. Two investigators independently screened the collected literature, extracted relevant data and assessed the quality of the literature. Review Manager 5.4 software was applied for data analysis. Twenty-nine RCTs with 1764 patients were included. According to the combined results, when compared with conventional treatment, HBOT significantly increased the complete healing rate of DFUs (46.76% vs. 24.46%, odds ratio [OR]: 2.83, 95% CI: 2.29–3.51, p < 0.00001) and decreased the amputation rate (26.03% vs. 45.00%, OR: 0.41, 95% CI: 0.18–0.95, p = 0.04), but the incidence of adverse events was significantly higher in patients (17.37% vs. 8.27%, OR: 2.49, 95% CI: 1.35–4.57, p = 0.003), whereas there was no significant difference in the mortality (6.96% vs. 12.71%, OR: 0.52, 95% CI: 0.21–1.28, p = 0.16). Our results suggest that HBOT is effective in increasing the complete healing rate and decreasing the amputation rate in patients with DFUs, but increases the incidence of adverse events, while it has no significant effect on mortality.

Effect of two different modalities of hysterectomy on wound infection and wound dehiscence in obese patients

Abstract

This research intended to investigate the influence of the operation of both kinds of hysterectomies in the risk of wound infection and the degree of wound dehiscence. Both of them were open field and laparoscope. In this research, we looked into four databases: PubMed, Web of Science, Embase and Cochrane Library. Research was conducted on various operative methods for hysterectomy in obese patients between 2000 and October 2023. Two independent investigators performed an independent review of the data, established the inclusion and exclusion criteria, and managed the results with Endnote software. It also evaluated the quality of the included literature. Finally, the data were analysed with RevMan 5.3. This study involved 874 cases, 387 cases received laparoscopy and 487 cases received open access operation. Our findings indicate that there is a significant reduction in the rate of post-operative wound infection among those who have received laparoscopy compared with who have received open surgical procedures (odds ratio [OR], 0.04; 95% confidence interval [CI], 0.01–0.15; p < 0.001); There was no statistical difference between the rate of post-operative wound dehiscence and those who received laparotomy compared with those who received open surgical procedures (OR, 0.33; 95% CI, 0.10–1.11; p = 0.07); The estimated amount of blood lost during the operation was less in the laparoscopy group compared with the open procedure (mean difference, −123.72; 95% CI, −215.16 to −32.28; p = 0.008). Generally speaking, the application of laparoscopy to overweight women who have had a hysterectomy results in a reduction in the expected amount of bleeding during surgery and a reduction in the risk of post-operative wound infections.

Efficacy of autologous platelet‐rich plasma combined with negative pressure sealing drainage in the treatment of patients with diabetic foot ulcer

Abstract

This study systematically evaluates the efficacy of autologous platelet-rich plasma (PRP) combined with negative pressure sealing drainage (NPSD) in the treatment of diabetic foot ulcers (DFU). A comprehensive computerized search was conducted in PubMed, Embase, Google Scholar, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases for randomized controlled trials (RCTs), from database inception to November 2023, on the treatment of DFU using autologous PRP combined with NPSD. Two researchers independently screened the literature, extracted data, and conducted quality assessments based on inclusion and exclusion criteria. Data analysis was performed using RevMan 5.4 software. A total of 17 RCTs involving 1325 DFU patients were included. The analysis revealed that the application of autologous PRP combined with NPSD in DFU patients significantly increased the ulcer healing rate (OR = 3.54, 95% CI: 2.71–4.62, p < 0.001) and the overall treatment efficacy rate (OR = 4.99, 95% CI: 3.46–7.19, p < 0.001), and significantly reduced the wound healing time (SMD = −2.05, 95% CI: −2.61 to −1.49, p < 0.001). This study indicates that the treatment of DFU with autologous PRP combined with NPSD accelerates wound healing, improves the overall treatment efficacy rate, and offers a new option for the management of DFU.

Clinical efficacy of ablative laser combined with pulsed dye laser in the treatment of pathological scars: A systematic review and meta‐analysis

Abstract

Objective

A systematic review and meta-analysis were conducted to evaluate the efficacy and safety of ablative laser combined with pulsed dye laser to treat pathological scars.

Methods

A systematic literature review was conducted to identify all blind, randomized, controlled trials of ablative laser and pulsed dye laser for treating pathological scars. The databases PubMed, Embase, and Cochrane were used. All research on ablative laser combined with PDL in treating pathological scars with ablative laser or no treatment as controls were included in the meta-analysis. The retrieved studies' reference lists were thoroughly examined.

Results

POSAS and VSS were used as evaluation criteria in seven studies involving 189 patients. Effect of combined laser group therapy (−1.259 95% confidence interval, −1.515 to −1.003; p < 0.0001). The difference between the combined treatment and control groups was (−1.375; 95% CI, −1.727 to −1.023; p < 0.0001) and (−1.150; 95% CI, −1.523 to −0.777; p < 0.0001).

Conclusions

Ablative laser combined with PDL is more effective and safer than ablative laser or PDL alone in the treatment of pathological scars.

Metabolic dysfunction‐associated fatty liver disease in the elderly with diabetic foot ulcers: A longitudinal cohort study

Abstract

This study aimed to explore the association between metabolic-associated fatty liver disease (MAFLD) and ulcer recurrence risk in patients with diabetic foot ulcers (DFUs) through an ambispective longitudinal cohort. From December 2013 to December 2022, a total of 482 inpatients with DFUs (PEDIS grade 3 and above with a severe infection) were eligible for inclusion in this study. This was an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 36 months. According to whether having MAFLD or not, all subjects were placed into two groups: non-MAFLD (n = 351) and MAFLD (n = 131). The association between MAFLD and ulcer recurrence in patients with DFUs was then evaluated through multivariate Cox regression analysis, stratified analyses and Kaplan–Meier survival analysis. Throughout the follow-up period, out of 482 subjects with DFUs, 68 had ulcer recurrence (14.1%). Three Cox regression models were established for data analyses. In the model I (unadjusted), MAFLD was significantly associated with the ulcer recurrence rate in patients with DFUs (HR = 1.79; 95% CI = 1.097–2.92; p = 0.02). Model II (adjusted model I with gender and age) (HR = 1.781; 95% CI = 1.09–2.912; p = 0.021) and model III (adjusted model II with CVD, duration of diabetes and Cr.) (HR = 1.743; 95% CI = 1.065–2.855; p = 0.027) also showed that MAFLD was significantly related to the ulcer recurrence risk in patients with DFUs, respectively. Stratified analysis indicated that subjects aged ≥60 had a greater risk of ulcer recurrence in MAFLD than in non-MAFLD (HR = 2.31; 95% CI = 1.268–4.206; p = 0.006). Kaplan–Meier survival curve analysis showed that ulcer recurrence rate had a significant association with MAFLD (log-rank, p = 0.018). This study indicated a close association between ulcer recurrence risk and MAFLD in patients with DFUs, especially in the elderly (aged ≥60). Therefore, special attention should be paid to the elderly with both DFUs and MAFLD because they have a higher ulcer recurrence rate than other general populations in routine clinical practice.

Assessing Mailuoning injection in wound healing and thrombophlebitis management: A rat model study

Abstract

Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.

A multicenter, randomized controlled clinical trial evaluating the effects of a novel autologous heterogeneous skin construct in the treatment of Wagner one diabetic foot ulcers: Final analysis

Abstract

A novel autologous heterogeneous skin construct (AHSC) was previously shown to be effective versus standard of care (SOC) treatment in facilitating complete wound healing of Wagner 1 diabetic foot ulcers in an interim analysis of 50 patients previously published. We now report the final analysis of 100 patients (50 per group), which further supports the interim analysis findings. Forty-five subjects in the AHSC treatment group received only one application of the autologous heterogeneous skin construct, and five received two applications. For the primary endpoint at 12 weeks, there were significantly more diabetic wounds closed in the AHSC treatment group (35/50, 70%) than in the SOC control group (17/50, 34%) (p = 0.00032). A significant difference in percentage area reduction between groups was also demonstrated over 8 weeks (p = 0.009). Forty-nine subjects experienced 148 adverse events: 66 occurred in 21 subjects (42%) in the AHSC treatment group versus 82 in 28 SOC control group subjects (56.0%). Eight subjects were withdrawn due to serious adverse events. Autologous heterogeneous skin construct was shown to be an effective adjunctive therapy for healing Wagner 1 diabetic foot ulcers.

Impact of robotic and open surgery on patient wound complications in gastric cancer surgery: A meta‐analysis

Abstract

This meta-analysis is intended to evaluate the effect of both robotic and open-cut operations on postoperative complications of stomach carcinoma. From the earliest date until June 2023, a full and systemic search has been carried out on four main databases with keywords extracted from ‘Robot’, ‘Gastr’ and ‘Opene’. The ROBINS-I instrument has been applied to evaluate the risk of bias in nonrandomized controlled trials. In these 11 trials, a total of 16 095 patients had received surgical treatment for stomach cancer and all 11 trials were nonrandomized, controlled trials. Abdominal abscesses were reported in 5 trials, wound infections in 8 trials, haemorrhage in 7 trials, wound dehiscence in 2 trials and total postoperative complications in 4 trials. Meta-analyses revealed no statistically significantly different rates of postoperative abdominal abscesses among patients who had received robotic operations than in those who had received open surgical procedures (OR, 0.91; 95% CI, 0.25, 3.36; p = 0.89). The incidence of bleeding after surgery was not significantly different from that in both groups (OR, 1.37; 95% CI, 0.69, 2.75; p = 0.37). Similarly, there was no significant difference between the two groups (OR, 0.78; 95% CI, 0.52, 1.18; p = 0.24). No significant difference was found between the two groups (OR, 1. 28; 95% CI, 0.75, 2.21; p = 0.36). No significant difference was found between the two groups of patients who had received the robotic operation and those who had received the surgery after the operation (OR, 1.14; 95% CI, 0.78, 1.66; p = 0.49). Generally speaking, this meta-analysis suggests that the use of robotics does not result in a reduction in certain postsurgical complications, including wound infections and abdominal abscesses. Thus, the use of a microinvasive robot for stomach carcinoma operation might not be better than that performed on the surgical site after the operation. This is a valuable guide for the surgeon to select the operative method.

Effect of mitomycin C and 5‐fluorouracil on wound healing in patients undergoing glaucoma surgery: A meta‐analysis

Abstract

Increased intraocular pressure (IOP) is a risk factor for glaucoma. One treatment option is trabeculectomy. Antimetabolic agents are used in the operation to decrease the post-operative scarring of the wound. The two most common medicines are Mitomycin C (MMC) and 5-Fluorouracil (5-FU). The aim of this research is to assess the effect of MMC on post-operation wound healing in comparison with 5-FU in addition to trabeculectomy. Well, we went through four common databases. Our language was limited to English during the study. The last time we looked at the e-databases was August 2023. Case control studies were performed where MMC resulted in better wound healing than 5-FU. Researchers selected a total of 1023 trials and eventually selected six trials for data analysis. Four hundred and ninety one cases of glaucoma were treated with trabeculectomy. Among them, 246 were given MMC and 245 were given 5-FU during operation. Six trials showed that there was no statistical difference between MMC and 5-FU in the incidence of post-operative wound leak in glaucoma patients who received trabeculectomy (OR, 1.21; 95% CI, 0.63–2.30 p = 0.57); Five trials demonstrated that MMC was associated with a reduced risk of post-operative corneal damage compared to 5-FU injection (OR, 0.18; 95% CI, 0.06–0.56 p = 0.003); In both trials, the incidence of post-operative bleeding was not significantly different from that of 5-FU injected in the MMC group (OR, 0.33; 95% CI, 0.05–2.16 p = 0.25). Our results indicate that MMC is superior to 5-FU in the reduction of post-operative corneal injury. Additional comparisons between MMC and 5-FU are required in order to increase the reliability and effectiveness of these findings.

Most individuals with diabetes‐related foot ulceration do not meet dietary consensus guidelines for wound healing

Abstract

The inaugural expert consensus and guidance for Nutrition Interventions in Adults with Diabetic Foot Ulcers (DFU) have been welcomed by clinicians internationally. This short report aimed to determine how the macronutrient and micronutrient status of individuals living with DFU compared to the American Limb Preservation Society Nutrition Interventions in Adults with DFU expert consensus and guidance. Descriptive analysis was conducted as a secondary analysis of an existing dataset. Mean (SD) dietary intake, the proportion meeting the nutrition recommendations and the proportion exceeding the upper limit (UL) for specific vitamins and minerals were reported. Most individuals with DFU do not meet current consensus guidelines for optimal dietary intake for wound healing, with inadequacies evident for fibre, zinc, protein, vitamin E and vitamin A. Future iterations of the consensus guideline should consider using evidence-informed recommendations for clinical practice, with the inclusion of all nutrients that are essential for wound healing in DFU.

A meta‐analysis of the risk factors of surgical site infection after hysterectomy for endometrial cancer

Abstract

Surgical Site Infection (SSI) is one of the common postoperative complications after hysterectomy for endometrial cancer (EC). Previous studies have investigated the risk factors for SSI in patients with EC. However, big differences in research results exist, and the correlation coefficients of different research results are quite different. A meta-analysis was conducted to examine the risk factors related to SSI in patients with EC. We searched English databases to collect case–control studies or cohort studies published before July 20, 2023, including PubMed, Web of Science, Embase and ScienceDirect. The risk of bias in the included studies was assessed via Newcastle–Ottawa Scale. The analysis was performed using RevMan 5.4.1 tool. A total of 6 articles (n = 3647) were selected in this meta-analysis. The following risk factors were presented to be significantly correlated with SSI in EC: laparotomy (OR = 2.66, 95% CI [1.57, 4.54]), postoperative blood sugar ≥10 mmol/L (OR = 4.38, 95% CI [2.83, 6.78]), Federation International of Gynaecology and Obstetrics (FIGO) stage-III or IV (OR = 2.27, 95% CI [1.49, 3.46]). The occurrence of SSI is influenced by a variety of factors. Thus, we should pay close attention to high-risk subjects and take crucial targeted interventions to lower the SSI risk after hysterectomy. Owing to the limited quality and quantity of the included studies, more rigorous studies with adequate sample sizes are needed to verify the conclusion.

Quercetin and its derivatives for wound healing in rats/mice: Evidence from animal studies and insight into molecular mechanisms

Abstract

Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta-analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, −3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL-1β, IL-10, TNF-α, TGF-β, vascular endothelial growth factor (VEGF), hydroxyproline and alpha-smooth muscle actin (α-SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition.

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